Papillomaviruses (PV) form a group of viruses associated with benign and malignant lesions of cutaneous and mucosal epithelia. So far, more than 100 different PV genotypes have been identified that infect humans. More than 30 of these human papillomavirus (HPV) types can be passed from person to person through sexual contact and are often called genital or mucosal HPVs. A further division of this group in low and high-risk types is made based on the association of the specific types with cervical cancer (1). Apart from these genital HPV types a second group of which approximately 48 types have been identified, exists that has a tropism for the cutaneous epithelia (2). These can be subdivided in classic wart types and the former B1 group, now designated as the beta-PV genus consisting of human PV (HPV) types 5, 8, 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, 36, 37, 38, 47, 49, 75, 76, 80, HPVcand92, 93 and HPVcand96. Recently found partial PV sequences indicate however that more than 35 new types have probably to be added to the 25 already known beta-PV types (3).
Originally, members of this genus have been found in skin lesions from patients with the rare hereditary disease epidermodysplasia verruciformis (EV). The disorder is characterized by numerous flat cutaneous warts, and a high-risk of cutaneous squamous cell carcinomas (SCCs) mostly localized on the sun-exposed areas of the skin. In contrast to the presence of multiple HPV types in the benign lesions, mostly HPV types 5 and 8 and sometimes HPV types 14, 17, 20 or 47 have been detected in the SCCs of EV-patients, which may be regarded as high-risk types (3).
HPV DNA detection, mainly by nested PCR, identified DNA from beta-PV types in 30-50% of SCCs in immunocompetent patients and in up to 80% of the SCCs in immunosuppressed patients, e.g. renal transplant recipients (4). These epidemiological studies based on HPV DNA detection delivered at the present no convincing evidence for the existence of high-risk beta-PV types analogous to the high-risk genital HPV types (5). This may be (partially) due to the frequently used nested PCR, since its sensitivity is not known for most individual types but probably varies with regard to individual types by several orders of magnitude. Misclassification by sequence analysis of the amplimers of the former MaHa PCR (5), especially when multiple types are present in lesions or plucked hairs, may also underlie this observation. Also the power of the epidemiological studies that were carried out until now may play a role.
Only little knowledge is available on the biological properties of the beta-PV types. As a result no more than speculations about the mechanism of beta-PV related carcinogenesis are possible. In contrast to cervical cancer, skin cancer related to HPV is probably caused by an interaction between beta-PV types and ultraviolet radiation. The early viral protein E6 of some types of beta-PV may impair the DNA repair process and prevent apoptosis after exposure to ultraviolet radiation (6, 7, and 8). As a result, beta-PV-infected, DNA-damaged cells may survive. This may ultimately lead to cutaneous (pre)malignant lesions like actinic keratoses and SCCs.
Establishing an association between one or more specific beta-PV types and premalignant and malignant lesions like solar keratoses and SCCs requires very large epidemiologic case-control and cohort studies involving the detection and genotyping of HPV DNA in a large number of samples, often containing multiple beta-PV types.
Several PCR-primer sets have already been developed to detect beta-PV types in skin biopsies, plucked hairs and skin swabs. Until now beta-PV genotyping is performed either by sequencing of broad spectrum PCR amplimers or by as type-specific PCRs. However, when typing of all the 25 known beta PV types is required in a large epidemiological study, a faster and more reliable method is required. Earlier experiences with the established SPF10-LiPA system show that a reverse hybridisation assay is well suited for this purpose (9).